Uterine cervical cancer is the second most common cancer among women worldwide, with nearly 500,000 new cases per year (Parkin et al., 2005). It caused an estimated 274,000 deaths in the year 2002 and it is one of the leading causes of cancer-related deaths in young women (zur Hausen, 2002). Cervical cancer typically results from cellular transformation after persistent infections with high-risk type human papilloma virus (HPV) (Scheffner et al., 1990). Almost all squamous cell carcinomas and the majority of adenocarcinomas of the stratified epithelium are HPV positive. Although HPV is capable of initiating cancer through the disruption of multiple tumor-suppressor pathways, alone it is not sufficient for the development of the fully transformed cancer phenotype (Burk, 1999). Additional host factors are required for the development of the malignant phenotype.
A precursor of cervical cancer is also called cervical dysplasia, which literally means abnormal cell growth. There are two different systems for classifying cervical dysplasia, the SIL (squamous intraepithelial lesion) system and the CIN (cervical intraepithelial neoplasia) system. Although what the systems describe is similar, they differ in some important respects. The SIL system looks only at individual cells, generally from a Pap test, and these cells are classified according to the degree of cell abnormality. According to the SIL system, cervical dysplasia is divided into AGUS or AGCUS (atypical glandular cells of undetermined significance), LSIL (low grade squamous intraepithelial lesion) and HSIL (high grade squamous intraepithelial lesion). In the CIN system, classification of cervical dysplasia is based both on the degree of dysplasia within the individual cells and the depth below the surface of the cervix to which the dysplasia extends. According to the CIN system, cervical dysplasia is divided into CIN1 (corresponding to mild dysplasia or LSIL), CIN2 (corresponding to moderate dysplasia or HSIL) and CIN3 (corresponding to severe dysplasia or HSIL). Most of CIN1 will regress back to normal tissue over time but about 11% of CIN1 will progress to CIN3. Only a very small percentage of CIN1 leads to cancer. About 43% of CIN2 will regress back to normal and 20% will progress to CIN3. Although some CIN3 will spontaneously regress, this dysplasia is almost always treated since the next step is cancer. CIN3 is sometimes also referred to as carcinoma in situ (CIS).
Three methods are widely used for the screening of cervical cancer and cervical dysplasia, cytology screening, visual inspection with acetic acid application (VIA) and HPV tests. Currently, no method is available to distinguish progressive CIN from that destined to regress. The over-treatment of screen positive women is common.
MicroRNAs (miRNAs) are species of small non-coding single-stranded regulatory RNAs that interact with the 3′-untranslated region (3′-UTR) of target mRNA molecules through partial sequence homology (Yekta et al., 2004). They participate in regulatory networks as controlling elements that direct comprehensive gene expression (Fatica et al., 2006). Bioinformatics analysis has predicted that a single miRNA can regulate hundreds of target genes, contributing to the combinational and subtle regulation of numerous genetic pathways (Hwang and Mendell, 2006; Lewis et al., 2005).
Altered levels of expression of miRNAs correlate with various cancers and the individual controlling elements are thought capable to act as either oncogenes or tumor suppressors (Chen, 2005). A global study on the distribution of miRNAs in human genome revealed that 50% of the annotated miRNA genes are located in the cancer-associated genomic regions known as “fragile sites” (Calin et al., 2004). Furthermore, numerous functional studies indicate that different miRNAs have distinct effects at different stages of cancer progression, from tumorigenesis (He et al., 2007; Voorhoeve et al., 2006) to cancer invasion and metastasis (Budhu et al., 2008; Ma et al., 2007). The deregulation of miRNA levels has been reported in cervical cancer (Lee et al., 2008; Wang et al., 2008), but the effects of individual deregulated miRNA species in cervical cancer are largely unexplored.
Deregulation of miR-133 has also been reported in a number of other diseases, including colorectal carcinoma (Bandres et al., 2006), tongue squamous cell carcinoma (Wong et al., 2008), esophageal squamous cell carcinoma (Guo et al., 2008) and pancreatic ductal adenocarcinoma (Szafranska et al., 2007).
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